Recent advances in understanding and treating COPD related to α1-antitrypsin deficiency

In the classical form of alpha1-antitrypsin (AT) deficiency, a point mutation in AT alters the folding of a liver-derived secretory glycoprotein and renders it aggregation-prone. In addition to decreased serum concentrations of AT, the disorder is characterized by accumulation of the mutant alpha1-antitrypsin Z (ATZ) variant inside cells, causing hepatic fibrosis and/or carcinogenesis by a gain-of-toxic function mechanism. The proteasomal and autophagic pathways are known to mediate degradation of ATZ. Here we show that the autophagy-enhancing drug carbamazepine (CBZ) decreased the hepatic load of ATZ and hepatic fibrosis in a mouse model of AT deficiency-associated liver disease. These results provide a basis for testing CBZ, which has an extensive clinical safety profile, in patients with AT deficiency and also provide a proof of principle for therapeutic use of autophagy enhancers.

The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure.

Alpha1-antitrypsin deficiency is a genetic disorder that affects about one in 2000-5000 individuals. It is clinically characterised by liver disease and early-onset emphysema. Although alpha1 antitrypsin is mainly produced in the liver, its main function is to protect the lung against proteolytic damage from neutrophil elastase. The most frequent mutation that causes severe alpha1-antitrypsin deficiency arises in the SERPINA 1 gene and gives rise to the Z allele. This mutation reduces concentrations in serum of alpha1 antitrypsin by retaining polymerised molecules within hepatocytes: an amount below the serum protective threshold of 11 micromol/L increases risk for emphysema. In addition to the usual treatments for emphysema, infusion of purified alpha1 antitrypsin from pooled human plasma represents a specific treatment and raises the concentrations in serum and epithelial-lining fluid above the protective threshold. Evidence suggests that this approach is safe, slows the decline of lung function, could reduce infection rates, and might enhance survival. However, uncertainty about the cost-effectiveness of this expensive treatment remains.